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• W2789746416 abstract "News & Views25 March 2018free access Heterochromatin and cohesion protection at human centromeres: the final say of a long controversy? Jean-Paul Javerzat [email protected] orcid.org/0000-0002-9671-6753 Institut de Biochimie et Génétique Cellulaires, UMR 5095, CNRS, Université de Bordeaux, Bordeaux Cedex, France Search for more papers by this author Jean-Paul Javerzat [email protected] orcid.org/0000-0002-9671-6753 Institut de Biochimie et Génétique Cellulaires, UMR 5095, CNRS, Université de Bordeaux, Bordeaux Cedex, France Search for more papers by this author Author Information Jean-Paul Javerzat1 1Institut de Biochimie et Génétique Cellulaires, UMR 5095, CNRS, Université de Bordeaux, Bordeaux Cedex, France EMBO Rep (2018)19:e45980https://doi.org/10.15252/embr.201845980 See also: Q Yi et al (April 2018) PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Mammalian centromeres are embedded within heterochromatin, a specialized chromatin assembled onto repetitive DNA that forms the primary constriction of chromosomes. In early mitosis, the bulk of cohesin dissociates from chromosomes, but a small fraction is spared at the centromere providing the ultimate linker between sister chromatid pairs, essential for their proper attachment to the mitotic spindle. Whether heterochromatin plays a role in the protection of centromere cohesion has long been controversial. In this issue of EMBO Reports, Yi et al show that heterochromatin protein 1 (HP1) isoforms α and γ act redundantly to protect mitotic centromere cohesion through the recruitment of the cohesion protector Haspin 1. Sister chromatid cohesion is mediated by the cohesin complex that is thought to capture replicated chromatids within its large ring-shaped structure formed by two coiled-coil SMC subunits (Smc1 and Smc3) bridged by Scc1 (Fig 1A). The interaction of the complex with DNA is antagonized by the cohesin-releasing factor Wapl, which together with the regulatory cohesin subunit Pds5 binds the complex and triggers DNA release through the opening of the Smc3–Scc1 ring interface, resulting in the dissociation of the cohesin complex from chromatin (Fig 1A). From the onset of DNA replication until mitosis, the cohesion factor Sororin binds cohesin and antagonizes Wapl to maintain sister chromatid cohesion. In the early stages of mitosis, the mitotic kinases Cdk1, Plk1, and Aurora B phosphorylate cohesin and Sororin, thereby re-activating Wapl-dependent cohesin release. The bulk of cohesin is removed from chromosomes at this stage, but a small fraction remains at centromeres, protected by the centromeric factors Shugoshin 1 (Sgo1) and Haspin. Sgo1 competes with Wapl for Scc1 binding, and recruits the protein phosphatase PP2A to keep the cohesin complex and Sororin in a hypo-phosphorylated state, while the Haspin kinase inhibits Wapl binding to Pds5 234. As cells progress to metaphase, the centromere becomes the ultimate link between sister chromatids, leading to the characteristic X shape of chromosomes when mitosis is artificially prolonged. At that time, a small amount of cohesin is left there, and appears to localize close to heterochromatin at pericentromeres, suggesting a role for heterochromatin in the protection of centromere cohesion. Figure 1. Heterochromatin Protein 1 α and γ recruit the cohesin protector Haspin to pericentromeres(A) The cohesin complex comprises two long coiled-coil SMC subunits bridged by Scc1. The complex can be removed from chromatin through the concerted action of SA2, Pds5B, and Wapl, which bind to cohesin and regulate DNA exit through the opening of the Smc3–Scc1 interface. (B) In early mitosis, the bulk of cohesin dissociates from the chromosomes, but a small amount remains at the centromere. The cohesin protector Haspin is recruited there through a dual interaction with cohesin and HP1. Haspin binds the cohesin complex through its Pds5 interacting domain (PIM) and the CSD of HP1 through the PxVxL motifs. The PIM competes with Wapl for Pds5 binding, and the kinase domain (KD) of Haspin phosphorylates Wapl and decreases its affinity for Pds5. Download figure Download PowerPoint Heterochromatin protein 1 (HP1) is a major component of heterochromatin. All HP1 isoforms share a common structural organization with a chromodomain (CD) and a chromoshadow domain (CSD) in the amino- and carboxy-terminus, respectively 5. The CD binds to di-/trimethylated histone H3 lysine 9 (H3-K9me2/3) nucleosomes, while the CSD acts as a dimerization module and as a receptor for proteins bearing PxVxL motifs. There are three HP1 isoforms in human (HP1-α, β, and γ). All three form foci in interphase nuclei. Upon mitotic entry, phosphorylation of histone H3 serine 10 disrupts the H3K9me–CD interaction, and most HP1 is removed from chromosomes. However, a small amount of HP1α and HP1γ remains at pericentromeric domains 5. Thus, very similar to cohesin, the bulk of HP1 is stripped off chromosomes early in mitosis except at the centromere, suggesting a role for HP1 in the protection of centromeric cohesion. However, HP1 knockdown experiments by various means led to conflicting results 678. Likewise, Sgo1 interacts with HP1α 9, suggesting that the pool of HP1 that remains at mitotic centromeres may be recruiting this cohesion protector. Although Yamagishi et al reported that depletion of HP1α by siRNA reduces Sgo1 localization at mitotic centromeres 9, another study found that a Sgo1 mutant deficient for HP1 binding was normally recruited to mitotic centromeres in human cells, and was proficient for cohesion protection 10. In this issue of EMBO Reports, Qi Yi et al revisit the role of HP1 in mammalian cells by a straightforward genetic approach, generating HP1α and HP1γ single- and double-knockout (DKO) HeLa cell lines using CRISPR/Cas9 1. While single-KO cell lines did not show detectable defects, the DKO cells displayed profound mitotic abnormalities, including loss of sister chromatid cohesion, increased inter-kinetochore distances, prolonged mitosis, and aberrant chromosome segregation. These defects were efficiently rescued by stable expression of either HP1α or HP1γ, indicating that the two isoforms act redundantly 1. The CSD of HP1 was crucial for its cohesion function, as CSD mutants of HP1α failed to complement the DKO phenotype, and the artificial tethering of the CSD to centromeres was sufficient to restore HP1 DKO-induced cohesion defects 1. Further, the authors found a clear link to protection of centromere cohesion, as they found that HP1 requirement for cohesion protection could be bypassed by inhibiting Wapl, or by the artificial tethering of Haspin to centromeres. In a series of convincing experiments, the authors demonstrate that HP1α helps to recruit Haspin to centromeres via a direct interaction between PxVxL motifs within the N-terminus of Haspin and the CSD of HP1 1. Based on these findings, and on those of previous studies, the authors propose a model in which full Haspin recruitment to centromeres is achieved through Haspin binding to HP1 (through its CSD) and cohesin (through Pds5, Fig 1B). Haspin then protects cohesion by phosphorylating Wapl, which decreases Wapl affinity for Pds5 3, and through its N terminal Pds5 interacting domain (PIM) that competes with Wapl for Pds5 occupancy 4. For high fidelity in chromosome segregation, cohesion must be released in the timely manner, and defects in this pathway have been linked to cancer 25. The simultaneous binding of Haspin to Pds5 and HP1 might ensure that cohesion is protected within pericentromeric chromatin at early stages of mitosis. It is striking that two overlapping, but non-redundant pathways seem to cooperate at that time to safeguard this. Sgo1 and Haspin target distinct Wapl binding sites on cohesin, and may use different anchors at the centromere, rendering the process very efficient. Still, many questions remain to be solved. Is this cooperation a means to provide robustness, or does this provide different functions in space and time? Do both proteins target the same pool of cohesin, or distinct cohesin populations within the same centromere? Does this process evolve from prophase to metaphase? The highly organized structure of centromeric chromatin suggests that besides sister chromatid cohesion, the cohesin complex may also promote centromere folding via DNA looping. Improvements in imaging techniques and protein mapping along centromeric repeats may help answer these questions in the future. Acknowledgements Work in Jean-Paul Javerzat laboratory is supported by funding from the Centre National de la Recherche Scientifique, l'Université de Bordeaux, la Région Aquitaine, l'Association pour la Recherche sur le Cancer (PJA 2017 1206 211), and l'Agence Nationale de la Recherche (ANR-14-CE10-0020-01). References 1. Yi Q, Chen Q, Liang C et al (2018) EMBO Rep 19: e45484Wiley Online LibraryPubMedWeb of Science®Google Scholar 2. Marston AL (2015) Mol Cell Biol 35: 634–648CrossrefCASPubMedWeb of Science®Google Scholar 3. Liang C, Chen Q, Yi Q et al (2018) EMBO Rep 19: 43–56Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 4. Zhou L, Liang C, Chen Q et al (2017) Curr Biol 27: 992–1004CrossrefCASPubMedWeb of Science®Google Scholar 5. Higgins JM, Prendergast L (2016) Dev Cell 36: 477–478CrossrefCASPubMedWeb of Science®Google Scholar 6. Serrano A, Rodriguez-Corsino M, Losada A (2009) PLoS One 4: e5118CrossrefCASPubMedWeb of Science®Google Scholar 7. Inoue A, Hyle J, Lechner MS et al (2008) Mutat Res 657: 48–55CrossrefCASPubMedWeb of Science®Google Scholar 8. Koch B, Kueng S, Ruckenbauer C et al (2008) Chromosoma 117: 199–210CrossrefCASPubMedWeb of Science®Google Scholar 9. Yamagishi Y, Sakuno T, Shimura M et al (2008) Nature 455: 251–255CrossrefCASPubMedWeb of Science®Google Scholar 10. Kang J, Chaudhary J, Dong H et al (2011) Mol Biol Cell 22: 1181–1190CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 19,Issue 4,April 2018Cover: This image illustrates two PINK1 molecules (pink) bound to the mitochondrial translocase of the outer membrane (pale brown). Using NMR and mass spectrometry, Rasool et al. discovered that PINK1 autophosphorylates in trans at a single serine, which enables its kinase domain to recognize ubiquitin and Parkin. Here, PINK1 is shown interacting with a tetraubiquitin chain (green), tethered to mitofusin (yellow). The phospho‐ubiquitin chains then recruit Parkin (blue) to sites of mitochondrial damage for repair initiation. From Shafqat Rasool, Jean‐François Trempe and colleagues: PINK1 autophosphorylation is required for ubiquitin recognition. Scientific image by Jean‐François Trempe, Shafqat Rasool and Luc Truong (McGill University, Canada).The molecular surfaces were rendered using the software Chimera (UCSF), and were derived from the structures of PINK1 (PDB 6EQI), Mfn1 (PDB 5GNS), K6‐diubuquitin (PDB 5OHP), Parkin (PDB 4K95), and the TOM complex (EMD 3761). Volume 19Issue 41 April 2018In this issue FiguresReferencesRelatedDetailsLoading ..." @default.
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